| Project/Area Number |
17H04338
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | Nagoya University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
鈴木 史朗 愛知県がんセンター(研究所), 婦人科, 部長 (20612758)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000)
Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
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| Keywords | 卵巣癌 / 腹膜播種 / 腹膜中皮細胞 / 化学療法抵抗性 / 癌関連腹膜中皮細胞 / 癌性腹膜炎 / 薬剤耐性 / 癌関連腹膜中皮 / トランスクリプトーム解析 / エクソソーム / 卵巣癌関連腹膜中皮 / エクソソーム解析 / メタボローム解析 / 腹膜微小環境 |
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| Outline of Final Research Achievements |
We reported how ovarian cancer (OvCa)-associated mesothelial cells (OCAMs) induce platinum-resistance in OvCa cells through direct cell-to-cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro co-culturing experimental models and in silico omics data analysis. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF-β1 stimulation. OCAMs can induce decreased platinum-sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell-to-cell interactions. Further, we also confirmed activation of Akt signaling in OvCa cells in contact with TGF-β1 stimulated peritoneum, using an in vivo mice model. Their results suggest that the tumor microenvironment, enhanced by direct cell-to-cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum-resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.
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| Academic Significance and Societal Importance of the Research Achievements |
卵巣癌の腹膜播種では、腹膜中皮細胞が腫瘍内へと侵入し、TGF-β1により間葉転換を引き起こすことで、卵巣癌関連腹膜中皮細胞（OCAM）へと変化することを見出した。また、OCAMと接することで、卵巣癌細胞はAktシグナルの活性化を通してプラチナ製剤への抵抗性を獲得することを発見した。こうしたメカニズムの要因となるOCAMを治療の標的とすることは、今後、腹膜播種を伴う進行卵巣癌における新たな治療法になると考えられる。
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